The alpha 7 nicotinic acetylcholine receptors (α7nAChRs) are rapidly desensitizing ligand-gated ion channels that are abundantly expressed in the cerebral cortex and the hippocampus, a limbic structure intimately linked to attention processing and memory formation. α7nAChRs modulate neurotransmitter release and are responsible for direct fast excitatory neurotransmission. At the cellular level, activation of α7nAChRs can regulate interneuron excitability, modulate the release of excitatory and inhibitory neurotransmitters, and contribute to neuroprotective effects.
Several lines of evidence indicate that attention and cognitive impairment, which are characteristic of neurological and psychiatric disorders such as Alzheimer's disease (AD), schizophrenia, Parkinson's Disease (PD), multiple sclerosis, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment (MCI), age associated memory impairment (AAMI), may involve degeneration or hypo-function of cholinergic input. Moreover, genetic linkage has identified α7AChRs as a predisposing factor related to sensory gating deficits. Thus, targeting the α7nAChRs represents a therapeutic strategy for ameliorating cognitive deficits associated with neurodegenerative and neuropsychiatric diseases.
A number of reports also suggest that α7nAChRs mediate protection against neurotoxicity induced by amyloid beta and excitotoxic insults. Peripherally, α7-nAChRs are expressed in macrophages and their stimulation is essential for inhibiting the release of proinflammatory cytokines (e.g. TNF-a, IL-1) via the cholinergic anti-inflammatory pathway which is triggered in response to signals from the vagus nerve. Thus, the clinical use of agonists of the α7nAChRs could also represent a strategy against inflammatory diseases.
Selective positive allosteric modulation (PAM) of the α7nAChR is a recent therapeutic approach for treating these disease states. A key advantage of this approach is that modulation only occurs in the presence of endogenous agonist thereby preserving the temporal and spatial integrity of neurotransmission. At least two different profiles of PAMs have been described thus far for α7nAChRs: Type I modulators that predominately affect the apparent peak current and agonist sensitivity, and Type II modulators that also cause a modification of the desensitization profile of agonist response. Several potent PAMs have been described (for example, 5-hydroxyindole, NS-1738) that increase acetylcholine sensitivity with only marginal effects on the desensitization kinetics of the α7nAChR channel. Others such as PNU-120596, show profound effects on receptor desensitization in addition to enhanced sensitivity to acetylcholine and increased current amplitude.

The present invention seeks to address some of the shortcomings of the prior art therapeutics and is directed to a new class of compounds which are thought to exhibit positive modulation of α7nAChR.